Pulse Brain · Growing Health Evidence Index
Peer-reviewed

Rare and common genetic determinants of metabolic individuality and their effects on human health

Praveen Surendran, Isobel D. Stewart, Victoria P. W. Au Yeung, Maik Pietzner, Johannes Raffler, Maria A. Wörheide, Chen Li, Rebecca F. Smith, Laura B. L. Wittemans, Lorenzo Bomba, Cristina Menni, Jonas Zierer, Niccolò Rossi, Patricia A. Sheridan, Nicholas A. Watkins, Massimo Mangino, Pirro G. Hysi, Emanuele Di Angelantonio, Mario Falchi, Tim D. Spector, Nicole Soranzo, Gregory Michelotti, Wiebke Arlt, Luca A. Lotta, Spiros Denaxas, Harry Hemingway, Eric R. Gamazon, Joanna M. M. Howson, Angela Wood, John Danesh, Nicholas J. Wareham, Gabi Kastenmüller, Eric B. Fauman, Karsten Suhre, Adam S. Butterworth, Claudia Langenberg

Nature Medicine · 2022

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Summary

) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of meta

Source type
Peer-reviewed study
DOI
10.1038/s41591-022-02046-0
Catalogue ID
SNmoj1xvqt-8ng2z0
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